Sequestosome-1 (SQSTM1/p62) is rich with protein-interacting domains, including an N-terminal PB1 domain, a ZZ-type zinc finger domain, a TRAF6-binding domain (TBS), the LC3-interacting region (LIR), the KEAP1-interacting region (KIR), and a C-terminal ubiquitin binding domain (UBA). While p62 may primarily act as a key adaptor for the degradation of protein aggregates, cytoplasmic bodies and malfunctioning organelles by selective autophagy, it continues to gain interest for its intimate and complex involvement in a number of cell signaling pathways and functions. Generally, p62 has been shown to play important roles in protein ubiquitination, triggering cell autophagy and apoptosis in tumorigenesis, and it is particularly implicated in the activation of the transcription factor NF-κB, p38MAPK and mTOR pathways that help regulate cell homeostasis.
Studies have revealed that p62 takes part in selective autophagy. Autophagy is a tightly regulated conserved catabolic process occurring in all cells and thus has important implications for cell homeostasis, development and immune response among other functions. For example, microtubule-binding tau proteins in neurons are transferred to proteasomes by p62. Interestingly, disruption of the p62 gene in mice results in a phenotype resembling Alzheimer's disease. Similarly, accumulations of aggregated mutant huntingtin protein, the pathological basis of Huntington's disease, have been found to contain p62 and deletion of its UBA domain increases cell death by mutant huntingtin. p62 has also been found in cytoplasmic aggregates described in Parkinson's disease and amyotrophic lateral sclerosis as well as in breast cancer tumors. Additionally, targeted deletion of mice p62 has been found to lead to insulin and leptin resistance, type 2 diabetes and obesity. As emerging evidence supports p62's implication in several varying diseases, thus targeting Sequestosome-1 (SQSTM1/p62) is highly significant for drug design and discovery.
It is known that p62 plays a key role in autophagy and cell signaling involving the NF-kB, p38MAPK and mTOR pathways. In particular, studies with p62-deficient mice have demonstrated that one p62 function is to control osteoclastogenesis and bone remodeling. Normal osteoclast function relies on this regulation of the NF-kB pathway by p62. The Z domain is implicated in this mechanism, as it binds to RIP1 protein, which contains a “death” domain that interacts with TNF receptor, which can then activate NF-kB and p38MAPK signaling. In light of these and previous findings, p62 is an attractive drug target for a myriad of diseases, particularly multiple myeloma (MM) and related cancers as well as other diseases such as neurodisorder and diabetics diseases.
Among the diseases mentioned above, MM is an incurable hematologic malignancy, characterized by the dysregulated proliferation of plasma cells and progressive bone destruction in up to 80% patients. Despite the introduction of novel and more potent treatment regimens including thalidomide and bortezomib, MM is still the second most prevalent hematological malignancy. As reported by the Leukemia & Lymphoma Society (Facts 2009-2010), both the MM patient number and new diagnosed cases have markedly increased each year. Therefore, novel therapeutics that effectively inhibits tumor growth and overcome conventional drug resistance are urgently needed.